Khan, Alaa Matooq Q; (2023) Genetic investigation of neuromuscular disorders and sporadic inclusion body myositis (sIBM). Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Neuromuscular disorders (NMDs) are a broadly defined group of heterogeneous disorders that can affect the structure and function of muscles and nerves. This thesis focuses on discovering novel genes and genetic risk factors in patients and families from diverse ethnic populations. The neuromuscular diseases that I have focused on include a large cohort of worldwide sporadic inclusion body myositis (sIBM) patients and identifying disease-causing genes for many families and patients with rare forms of neuromuscular disorders through an integrated approach combining SNP genotyping-microarray, triplet repeat primed PCR, NGS technology, computational, and bioinformatics methods. Based on the Myositis Genetics Consortium (MYOGEN), we collected the largest sIBM cohort of blood and muscle tissue in the world as part of this thesis. The first whole-exome association analysis and burden tests were carried out. This described statistically significant SNPs on chromosome 6p22.1, a region containing genes associated with inflammation and infection. Subsequently, the first genome-wide association study (GWAS) was performed. This reported a statistically significant association with HLA-DQA1 in addition to discovering a novel association with genes implicated in inflammatory or neurodegenerative pathways. These data demonstrated further confirmation of the involvement of inflammatory and neurodegenerative pathways in sIBM pathogenesis. As part of the international SYNaPS project, WES was performed on 13 families with rare neuromuscular disorders to identify a disease-causing gene. I discovered a novel gene, SORD, which was the main cause of hereditary neuropathy in two patients. Additionally, I identified novel pathogenic mutations in the known or candidate genes NEFL, FGD4, MTMR2, GAN, WINK1, SH3TC2, LAMA2, and SGCG. The novel mutation in NEFL has expanded the clinical and mutational spectrum of AR-CMT due to the pathogenic NEFL mutation. An intensive genetic analysis was performed on 50 patients who remained genetically undiagnosed after routine clinical care at NHNN. I re-analysed their data generated as part of the UK 100,000 genome project and diagnostic panels, looking for candidate 4 genes to achieve the molecular diagnosis. This integration improved the molecular diagnosis in most patients. The known mutations in INF2 and MPV17 have expanded the clinical spectrum of the associated disease. The detailed phenotype of five patients suggested CANVAS syndrome, which guided us to test and confirm the pathogenic allele expansion in RFC1. The collection of a large series of sIBM has been shown in this thesis to reveal important genetic risk factors and will be an important resource for the future. The WES and GWAS-based SNP arrays were demonstrated to be important in sIBM and to be an effective method to investigate the genetic structure of rare complex muscle disorders.

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